Review of Epithelial-Mesenchymal Plasticity (EMP) in Cancer: Targeting EMT-MET Double-Bind by Combinations, Timing, and Sequencing (CTS) Strategy

Epithelial–mesenchymal transition (EMT) and its reverse, mesenchymal–epithelial transition (MET), are core cellular processes that drive epithelial–mesenchymal plasticity (EMP) in cancer. EMP regulates how tumor cells switch between detached and proliferative states, affecting cancer progression, spread, and resistance to treatment. Cancer cells gain invasive traits during EMT, enabling their escape from the primary site. At the same time, MET allows seeded cancer cells at distant sites to reacquire epithelial characteristics necessary for growth at secondary locations. These transitions are regulated by interconnected signaling pathways such as TGF‑β, Wnt/β‑catenin, and Notch, coordinated by master transcription factors including Snail, ZEB, and Twist. The tumor microenvironment—particularly hypoxia, inflammatory cues, and microRNA regulators like the miR‑200 family—modulates these processes, fostering hybrid epithelial/mesenchymal phenotypes that underlie tumor heterogeneity and therapy resistance. Addressing EMP requires multi-level therapeutic strategies and smart targeting reprogramming of transitional states, especially by incorporating epigenetic modifiers into the treatment protocol. This review describes a Combination, Timing, and Sequencing (CTS) framework to leverage EMP dynamics to improve cancer treatment outcomes while minimizing toxicities.